tbuckley/cabot-search huggingface dataset:
CSIG-14. THE IMPACT OF CORTICOTROPHIN RELEASING HORMONE STRESS NEURO-HORMONES ON THE VIABILITY AND PROLIFERATION OF BRAIN TUMOURS
Authors: Ana Rita Monteiro, Jerome Swinny
Journal: Neuro-Oncology (2023)

Abstract The majority of brain tumour sub-types are of glial origin. These include high-grade gliomas (HGGs), which lack effective targeted therapies and are thus invariably lethal. We have shown that stress leads to proliferation of brain glia. Such stress-induced glial cell division could provide opportunities for detrimental genetic mutations which increase the risk of oncogenesis. Identifying stress-induced glial plasticity could uncover molecular targets that directly influence glioma viability. Corticotropin-releasing hormone (CRH) stress neurohormones, including urocortin I-III (UCN I-III) are key mediators of stress signalling in the brain including neuroplastic processes. The aims of this project were to compare the expression CRH peptides and receptors in different types of brain tumours and their impact on cells viability and proliferation. Five different brain tumour cell lines were used (two biopsy-derived-in-house-established HGGs – UP007 and SEBTA023 – and three commercially available Medulloblastomas, MBs – UW402, CHLA-01-MED and CHLA-01R-MED). The gene expression profiles of the CRH family were accessed by qRT-PCR (n = 5) and the protein expression by Immunocytochemistry and flow cytometry (FC, n = 3). The effects of targeted drug modulation were assessed through viability (MTS, n = 3) and proliferation assays (Cyquant NF cell proliferation, n = 3). Statistical significance of qRT-PCRs and FC were calculated through a Kruskal-Wallis test, and for viability and proliferation assays through a two-way ANOVA approach. Values of P &amp;lt; 0.05 were accepted as significant. The qRT-PCRs revealed a higher expression of stress neuro-hormones mRNA in MBs compared to HGGs. Immunocytochemistry confirmed the protein expression of CRH and downstream receptors in all cell lines, while FC revealed a higher expression of CRH-Rs in HGGs than MBs. The pharmacological modulation of CRH-Rs induced contrasting effects on cellular viability and proliferation, suggesting patient-specific CRH-CRH-R pathway. This raises the prospect of repurposing available CRH-R ligands for targeted treatment of susceptible tumour types.
RTID-05. SURGICAL WINDOW OF OPPORTUNITY TRIAL REVEALS MECHANISMS OF RESPONSE AND RESISTANCE TO NAVTEMADLIN (KRT-232) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Veronica Rendo, Eudocia Lee, Connor Bossi, Nicholas Khuu, Sangita Pal, Abigail Reynolds, Auriole Fassinou, Keith Ligon, Rameen Beroukhim, Patrick Wen, Michelle Rudek
Journal: Neuro-Oncology (2023)

Abstract Over half of glioblastoma multiforme (GBM) patients retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, resulting in downstream pathway signaling and cell fate decisions such as growth inhibition and death from cellular stress. We have analyzed clinical samples from 21 patients with recurrent GBM treated with the MDM2 inhibitor KRT-232, all of which relapsed despite the biological promise of this small molecule. By analyzing on-treatment biopsy samples, we detected upregulation of p53 transcriptional targets, suggesting blood-brain barrier penetrance and drug pharmacodynamics. However, in patient-derived cell lines, treatment with KRT-232 at the clinically achieved concentration was only sufficient to stall but not reduce tumor growth. Cell death via apoptosis was achieved in these cell line models when MDM2 inhibition was combined with the chemotherapeutic agent temozolomide. These drugs have non-overlapping mechanisms of action and exhibit synergy in our cell line models. Normal human bone marrow cells underwent a reversible growth inhibition phenotype when treated with KRT-232 and TMZ, supporting the idea that a therapeutic window exists with this combination. We additionally observed that tumor progression occurred in the absence of p53 inactivating mutations, suggesting that other mechanisms of resistance to KRT-232 may modulate drug response and resistance in GBM. Indeed, drug treatment induced an adaptive response in human tumors, characterized by the upregulation of genes involved in glial cell differentiation processes. Ongoing work is focused on understanding how tumor heterogeneity and cell state modulate response and resistance of GBMs to MDM2 inhibition and other therapeutic strategies that reactivate p53 signaling. Our study highlights the utility of tissue sampling during clinical trials and represents the first clinical effort to detect adaptive changes in human tumor tissue associated with p53 reactivation.
EPID-19. THE INFLUENCE OF FACILITY TYPE ON INTRACRANIAL MENINGIOMA TREATMENT AND OUTCOMES: PREDICTING OVERALL SURVIVAL USING THE NATIONAL CANCER DATABASE
Authors: Nolan Brown, Sachiv Chakravarti, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract There is a growing body of evidence demonstrating improved outcomes for patients with CNS neoplasms treated at academic centers (ACs) versus non-academic centers (non-ACs). This represents a potential healthcare disparity within neurosurgery. Herein, we investigate the relationship between facility type and surgical outcomes in meningioma patients. METHODS: The National Cancer Database was queried for adult patients diagnosed with intracranial meningioma requiring intervention between 2004 and 2019. Patients were stratified by facility type and the Mann-Whitney U and Fisher exact tests were used for bivariate analysis of continuous and categorical variables. Multivariable logistic and linear regression were used to assess whether demographic variables predicted treatment at non-ACs. Furthermore, multivariate cox proportion hazard and log-rank tests were used to determine whether facility type was related to overall survival (OS). RESULTS: In total, 314,651 patients diagnosed with meningioma were included; 122,112 (38.8%) patients were treated at an AC and 192,539 patients (61.2%) were treated at a non-AC. On bivariate analysis, patients treated at an AC were more likely to be white (30.7% vs 24.7%, p&amp;lt; 0.001), have an income higher than $63,000 (31.8% vs 29% p&amp;lt; 0.001) and have a larger tumor (43.3±113.6 vs 39.3±106.8, p&amp;lt; 0.001). On multivariate Cox models, the risk of death for patients treated at ACs was 16.7% lower than that of non-AC patients (HR = 0.883, 95% CI 0.858–0.908, p &amp;lt; 0.001). When controlling for demographic and clinical variables, patients treated at ACs were more likely to undergo surgical intervention (OR = 1.059, 95% CI 1.033-1.087, p &amp;lt; 0.001) but less likely to receive radiotherapy (OR = 0.921, 95% CI 0.897-0.947, p &amp;lt; 0.001). CONCLUSIONS: Our results indicate that AC facility type is associated with disparate survival outcomes in treatment of intracranial meningiomas. Namely, patients treated at non-ACs appear to suffer a survival disadvantage.
INNV-05. OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS WITH RADIATION NECROSIS FOLLOWING GAMMATILE BRACHYTHERAPY IMPLANTATION
Authors: D Jay McCracken, Courtney McCracken, Tyler Kenning, Adam Nowlan, Erin Dunbar
Journal: Neuro-Oncology (2023)

Abstract Implantation of collagen tile brachytherapy GammaTile (GT Medical Technologies Tempe, AZ) allows for targeting of radiation to residual malignancy following surgical resection of gross disease. Radiation necrosis (RN) can develop after radiotherapy or brachytherapy. We sought to determine outcomes in recurrent glioblastoma patients with RN after treatment with Gammatile. All patients were previously treated with surgical resection followed Stupp protocol chemoradiation. At recurrence, patients underwent repeat surgical resection and implantation of GammaTile. Subsequent MRIs were assessed for stability, presumed RN or progression. Symptomatic RN patients were treated with corticosteroids or bevacizumab. From December 2020 to February 2023, 19 patients were treated. Median time from initial radiation to GammaTile therapy was 270 days. A total of 8 patients (42%) developed RN at a median time of 81 days from GammaTile. In RN patients vs those that did not develop RN, pathological tumor viability was lower (20% vs 50%, p=0.3), age was lower (54 vs 63, p=0.06), tumor volume was lower (10.8 cc vs 51.9 cc, p=0.02), time from initial surgery was longer (470 days vs 299 days, p=0.46), number of GammaTiles placed was lower (5 vs 8, p=0.045), rate of gross total resection (GTR) was higher (100% vs 64%, p=0.04), and MGMT methylation rate was higher (63% vs 11%, p=0.03). No patients in the RN group experienced radiographic progression (0% vs 45%, p=0.009) and 3 (38%) required bevacizumab therapy. Median overall survival from GammaTile surgery in the RN group was 325 days vs 188 days (p=0.03). Our series demonstrates a significant survival benefit in patients who develop RN following GammaTile implantation after glioblastoma recurrence. RN developed in younger patients with smaller tumor volumes, lower pathological tumor viability, and higher rates of GTR and MGMT methylation status.
DNAR-05. EXCEPTIONAL RESPONDERS TO BASE EXCISION REPAIR (BER) INHIBITION FOR RECURRENT GLIOBLASTOMA DISPLAY ENRICHMENT FOR DNA DAMAGE RESPONSE PATHWAYS: RNA SEQUENCING ANALYSIS FROM A MULTICENTER TRIAL
Authors: Ahmad Ozair, Jan Drappatz, Xiaobu Ye, Michael Berens, Sen Peng, Sanhita Rath, Harshil Dhruv, Tobias Walbert, Matthias Holdhoff, Glenn Lesser, Timothy Cloughesy, Andrew Sloan, Marta Couce, David Peereboom, Burt Nabors, Patrick Wen, Lisa Rogers, Stuart Grossman, Manmeet Ahluwalia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Therapies for glioblastoma recurrence after surgery and chemoradiation are warranted. TRC102 (methoxyamine), a small molecule DNA base-excision repair (BER) inhibitor, reverses temozolomide (TMZ) resistance in preclinical glioma models. We had investigated efficacy of TRC102+TMZ for recurrent glioblastoma (rGBM) through a multicenter trial. This work sought to report translational findings from RNA sequencing performed on patients with available tumor tissue. METHOD: A two-arm, two-stage, non-randomized, Phase II trial of TRC102+TMZ for adults with rGBM named BERT was conducted. Arm 1 included bevacizumab-naive patients at first recurrence, with primary aim of estimating response rates using RANO criteria. If sufficient activity was identified, arm 2 was planned in bevacizumab-refractory patients. Secondary aims were to determine overall survival (OS), progression-free survival (PFS), 6-month PFS, and toxicity. Exploratory aims were correlating clinical outcomes with MPG expression and MGMT methylation. Differential gene expression profiling was analyzed using DESeq2 GSVA (RRID:SCR_015687) and transformed into enrichment scores for 'hallmark of DNA repair' pathways from Molecular Signatures Database (MSigDB, RRID:SCR_016863) to assign mechanistic signatures of therapeutic vulnerability. RESULTS Arm 1 enrolled 19 patients with median of two treatment cycles, but objective responses were not observed. Hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). MGMT promoter was unmethylated in 14/19 patients, and MPG expression was present in 8/14 cases with available tumor tissue. MGMT methylation and MPG non-expression were associated with better OS and PFS. However, two ‘exceptional responders’ had PFS ≥11 months, with MGMT methylated and MPG expressed. RNA sequencing of their tumor tissue demonstrated significant enrichment for DNA damage response (DDR) pathways (MSigDB), chromosomal instability gene signatures (CIN70, CIN25), and proliferative gene signatures (PCNA25). CONCLUSION rGBM patients with elevated levels of MPG and DDR molecular signature may have impaired BER and respond better to TRC102+TMZ.
CSIG-15. PTN-PTPRZ1 SIGNALING MEDIATES TUMOR-NORMAL CROSSTALK IN GLIOBLASTOMA
Authors: Ryan Kan, Weihong Ge, Can Yilgor, Nicholas Bayley, Christopher Tse, Andrew Tum, Kunal Patel, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most devastating form of brain cancer with poor patient prognosis and high recurrence. An increasing body of literature suggests crosstalk between tumor and its surroundings, both molding the immune microenvironment and forming functional synapses with neighboring normal cells. Despite the high intra-tumoral and inter-patient heterogeneity, we have discovered PTN-PTPRZ1 signaling as the most significant and preserved communication pathway between GBM cells and their immediate neighboring cells. Through a novel tumor transplantation protocol onto cortical organoids, which are human embryonic stem cell-derived aggregates that faithfully mimic the human brain, we have seen evidence of tumor-normal crosstalk where PTN-PTPRZ1 is a key signaling axis. We hypothesize that PTN-PTPRZ1 signaling is pivotal to tumor growth and invasion, which ultimately leads to recurrence. Modulating PTN and/or PTPRZ1 levels on the cortical organoids via shRNA affects PTN and/or PTPRZ1 expression on the tumors, suggesting dynamic communication between tumor and normal cells via PTN-PTPRZ1 signaling. During the process of generating PTN knockdown cortical organoids, we have additionally discovered a pivotal role for PTN in the very early stages of cortical development. PTN and PTPRZ1 are signature markers of the outer radial glia in the developing human brain, which are absent in mouse models where the majority of PTN biology has been studied. By supplementing exogenous PTN to PTN knockdown organoids and withdrawing it at various timepoints, we have identified drastic phenotypes of neuron and radial glia survival and cell fate specification. With cortical organoids, we can interrogate the role of PTN in the early stages of neurodevelopment via a human-derived system.
CTNI-17. APPLICATION OF THE GBM-X DATA PLATFORM TO ESTIMATE TREATMENT EFFECTS OF THE EXPERIMENTAL THERAPIES OF THE RANDOMIZED PHASE 2 INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPIES
Authors: Rifaquat Rahman, Lorenzo Trippa, Geoffrey Fell, Eudocia Lee, Isabel Arrillaga-Romany, Mehdi Touat, Jan Drappatz, Mary Welch, Evanthia Galanis, Manmeet Ahluwalia, Howard Colman, Burt Nabors, Jaroslaw Hepel, Heinrich Elinzano, David Schiff, Ugonma Chukwueke, Rameen Beroukhim, Lakshmi Nayak, Jose Ricardo McFaline-Figueroa, Tracy Batchelor, Mikael Rinne, Thomas Kaley, Christine Lu-Emerson, Ingo Mellinghoff, Wenya Linda Bi, Omar Arnaout, Pier Paolo Peruzzi, Daphne Haas-Kogan, Shyam Tanguturi, Daniel Cagney, Ayal Aizer, Lisa Doherty, Sandro Santagata, David Meredith, E Antonio Chiocca, David Reardon, Brian Alexander, Keith Ligon, Patrick Wen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. METHODS INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects. RESULTS On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA. CONCLUSION In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.
PATH-34. CLINICOPATHOLOGIC CHARACTERIZATION OF DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA, H3-WILDTYPE AND IDH-WILDTYPE: AN AGGRESSIVE AND GENOMICALLY COMPLEX GROUP OF TUMORS AFFECTING CHILDREN AND ADULTS
Authors: Zhichao Wu, Rust Turakulov, Hye-Jung Chung, Karen Dazelle, Zied Abdullaev, Felipe D'Almeida Costa, Osorio Lopes Abath Neto, Nitin Wadhwani, Qinwen Mao, Lorraina Robinson, Michael Marshall, Matthew Frosch, Sahara Cathcart, Sanda Alexandrescu, Igor Fernandes, Matthew McCord, Craig Horbinski, Diana Thomas, Peter Pytel, Kyle Conway, Jason Gregory, Jeffrey Nirschl, Hannes Vogel, Krishnan Chandra, Murat Gokden, Calixto-Hope Lucas, Yelena Wilson, Peng Han, Abigail Goodman, Sonika Dahiya, Alexander Vortmeyer, Martha Quezado, Kenneth Aldape, Patrick Cimino
Journal: Neuro-Oncology (2023)

Abstract Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (pHGG) was newly introduced in the 2021 WHO CNS5. pHGG is further divided into distinct methylation subtypes (MYCN, A/B, RTK1, RTK2). Compared to adult-type diffuse gliomas, relatively little is known about pHGG, especially in the adult population and we therefore aimed to more fully understand the clinicopathological spectrum of pHGG. Our cohort of methylation-profiling-confirmed pHGGs (n=299) included pediatric (n=211) and adult (n=88) populations (age range=0-79 years). The mean age was highest in the A/B subtypes (27.7 years) and lowest in the MYCN subtype (13.5 years). Median survival (18 months for the entire cohort), MGMT promoter methylation status, and history of prior radiation did not differ between the pediatric and adult populations. MGMT promoter methylation was highest in RTK1C (51%) and lowest in subtype A (0%). All those with history of prior radiation (n=37) were classified as RTK1, with subclass distribution differing between patients with history of prior radiation (RTK1A=7.3%, RTK1B=41.8%, RTK1C=50.9%) versus those without (RTK1A=41.8%, RTK1B=21.5%, RTK1C=36.7%). Interestingly, the genomic somatic copy number alteration (SCNA) load did not differ for RTK1 based on prior radiation history status. However, adult pHGG did harbor a higher SCNA load than pediatric pHGG (p&amp;lt; 0.01). The higher SCNA load was driven by genomic copy number losses rather than amplifications, including adult pHGG harboring more CDKN2A/B and RB1 deletions. Amplifications of MET, CDK4, PDGFRA, MYC, and KIT were present across all subtypes, but were enriched in RTK1. MYCN amplification was enriched in the MYCN subtype. EGFR, MDM4, and CDK6 amplifications did not have subtype predilection. Overall, while the pediatric and adult pHGG have similar outcomes, there are differences in their genomic structures, most notably in adult pHGG harboring a higher SCNA load. Overall, pHGG represent a biologically diverse set of clinically aggressive tumors that warrant further intensive study.
NIMG-26. DIFFERENTIATION OF <i>IDH</i>-WILDTYPE GLIOBLASTOMA AND TUMEFACTIVE MULTIPLE SCLEROSIS USING PRE-OPERATIVE BRAIN MRI AND DEEP LEARNING: RIGOROUS AND UNBIASED EXPERIMENTAL DESIGN AND ANALYTICAL APPROACH
Authors: Gian Marco Conte, Paul Decker, Matthew Kosel, Thomas Kollmeyer, Christina McCarthy, Jessica Sagen, Yalda Nikanpour, Mahboubeh Fereidan-Esfahani, Bradley Erickson, Robert Jenkins, Daniel Lachance, W Oliver Tobin, Jeanette Eckel-Passow
Journal: Neuro-Oncology (2023)

Abstract Clinical management of IDH wildtype glioblastoma (GBM) and tumefactive multiple sclerosis (tMS) is drastically different. GBM requires maximal safe resection followed by chemoradiation, while tMS outcome is worsened by surgery and radiotherapy. Misdiagnosis of brain lesions may expose patients to unnecessary anxiety, surgery, or radiotherapy. Noninvasive methods to help with accurate diagnosis of tumor and non-tumor etiologies are needed. tMS subjects were identified by the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology (CMSAN). GBM subjects were matched to tMS by age at diagnosis, index MRI date, and sex. Inclusion criteria included one cm minimal lesion size and pre-operative post-contrast T1 and T2 images available for analysis. To identify potential experimental design bias, MRI technology and clinical characteristics were compared across groups. A 3D-DenseNet121 was used to develop a classification model using prespecified parameters: 600 epochs, batch size 16, learning rate 10-3, cross entropy loss, and AdamW optimizer. The stopping rule was defined as three sequential epoch cross entropy loss &amp;lt; 0.02. Five-fold cross validation (CV) was utilized to obtain an unbiased estimate of predictive performance (overfitting) and sensitivity of the 3D-DenseNet121 algorithm was evaluated. 224 subjects (114 GBM, 110 tMS) were analyzed: 40% male, median age 46. After one round of CV, the average unbiased estimate of sensitivity and specificity for predicting GBM from the final classification model was 0.86 and 0.73, respectively. To assess the reproducibility of the deep learning algorithm (3D-DenseNet121), the exact same CV folds were rerun resulting in average sensitivity and specificity of 0.82 and 0.75, respectively. Obtaining unbiased estimates of model performance using internal validation is critical before evaluating a final model on an external dataset. Understanding sensitivity of a deep learning algorithm is important for model validity. Differentiation of GBM and tMS appears reasonable with MRI; external validation is in progress.